Multiple Oncology/Hematology Indications Recommended by EMA in June

On 28 June 2018, the European Medicines Agency (EMA) issued positive opinions for approval of several new anticancer therapies in Europe.


  • Neratinib for Extended Adjuvant Therapy in HER2-Positive, HR-Positive Early Breast Cancer. The EMA granted a positive opinion to pan-HER targeted tyrosine kinase inhibitor neratinib (Nerlynx®, Puma) for use as an extended adjuvant therapy in patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor (HR)-positive breast cancer who are less than one year from the completion of prior adjuvant trastuzumab-based therapy. This positive opinion comes upon re-examination of the negative opinion issued by the EMA in February 2018. However, the positive opinion is restricted to patients with HR-positive disease. In the phase III ExteNET trial, 1 year of neratinib treatment following standard trastuzumab-based therapy was associated with significantly higher rates of 2-year invasive disease-free survival, compared to placebo (iDFS, 93.9% vs 91.6%; HR 0.67, P = .0091). This improvement in iDFS was maintained after 5 years (iDFS 90.2% vs 87.7%, HR 0.73, P = .008). In the HR-positive population, 5-year iDFS was 91.2% with neratinib, compared to 86.8% (HR 0.60, P = .002). While in HR-negative patients, the benefit was transient and diminished after cessation of treatment. The most common grade 3/4 treatment-related adverse event in ExteNET trial was diarrhea (40%), but this can be substantially reduced with appropriate antidiarrheal prophylaxis.
  • Lenvatinib as First-Line Alternative to Sorafenib in Hepatocellular Carcinoma. The EMA recommended expanding the indication of lenvatinib (Lenvima®, Eisai) to include use as a monotherapy for the treatment of newly-diagnosed advanced or unresectable hepatocellular carcinoma (HCC). This recommendation was based on results of the phase III REFLECT trial, in which lenvatinib demonstrated noninferiority compared to standard-of-care sorafenib in terms of overall survival (OS) (13.6 months vs 12.3 months; HR 0.92). In addition, lenvatinib showed significant improvement of progression-free survival (PFS), time to progression, and objective response. The most common treatment-related grade 3 or higher adverse events associated with lenvatinib were hypertension, diarrhea, decreased appetite, and weight loss. Lenvatinib is currently approved in Japan for this indication, but it has not yet received approval in the United States.
  • Adjuvant Nivolumab for Melanoma. The PD-1 inhibitor nivolumab (Opdivo®, Bristol-Myers Squibb) received a positive opinion for use as an adjuvant therapy following complete resection for patients with melanoma with lymph node involvement or resectable metastatic melanoma. In the phase III CheckMate-238 trial, adjuvant nivolumab significantly improved the 12-month recurrence-free survival (RFS) rate, compared to ipilimumab (70.5% vs 60.8%; HR 0.65, P<.001). Importantly, nivolumab was associated with lower rates of grade 3/4 treatment-related adverse events than ipilimumab (14.4% vs 45.9%).
  • First CAR-T Cell Therapies Recommended for Approval for Some Hematologic Malignancies . The EMA issued positive opinions for the approval of two CD19-targeting chimeric antigen receptor modified (CAR) T-cell therapies for hematologic malignancies. Axicabtagene ciloleucel (Yescarta™, Kite Pharma) is intended for the treatment of diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL), while tisagenlecleucel (Kymriah™, Novartis) is recommended for treatment of acute lymphoblastic leukemia (ALL) and DLBCL. The most common side effect in patients treated with CAR T cells is cytokine release syndrome (CRS), which can be fatal if not appropriately managed. In conjunction with these approvals, the EMA recommended expanding the indication of the monoclonal antibody tocilizumab (RoActemra®, Roche) to include management of CAR T cell–induced CRS. All these agents are already available in the United States.
  • Liposomal Chemotherapy Combo Given Nod for AML. CPX-351 (Vyxeos®, Jazz Pharmaceuticals), a liposomal formulation of daunorubicin and cytarabine chemotherapy, received a positive opinion for treatment of acute myeloid leukemia (AML). In a pivotal phase III trial, CPX-351 resulted in a 31% reduction in the risk of death, compared to standard daunorubicin and cytarabine (9.56 months vs 5.95 months; HR 0.69, P = .005).


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